US3954730A - 6-(Substituted-cycloalkylcarboxamide) penicillanic acids - Google Patents

6-(Substituted-cycloalkylcarboxamide) penicillanic acids Download PDF

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US3954730A
US3954730A US05/516,359 US51635974A US3954730A US 3954730 A US3954730 A US 3954730A US 51635974 A US51635974 A US 51635974A US 3954730 A US3954730 A US 3954730A
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mol
acid
acid chloride
sodium salt
chloro
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Karl Georg Metzger
Gunther Schmidt
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

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  • the present invention relates to penicillins, to a process for their production, pharmaceutical compositions wherein said penicillins are the active ingredient, and to methods of treating bacterial infections in humans and animals which comprises administering said compounds to such humans or animals.
  • the present invention includes growth-promoting compositions wherein said penicillins are the active ingredients and animal fodders, including methods of improving fodder utilization in animals utilizing said penicillins.
  • 6-amino-penicillanic acid derivatives exhibit good antimicrobial activity.
  • compounds in which halogen-substituted alicyclic carboxylic acids have been condensed with 6-aminopenicillanic acid (6-APA) have not been disclosed.
  • the present invention is concerned with penicillins of the formula ##SPC2##
  • R 1 and R 2 are the same or different and each is hydrogen, fluorine, chlorine or bromine; or when R 2 is hydrogen, R 1 can also be cyano, hydroxyl, azido, amino or nitro; or
  • R 1 and R 2 are bonded to a ring carbon atom and constitute a single oxygen atom
  • R 3 is hydrogen, methyl, chlorine, bromine, cyano, methoxy or carboxyl
  • n 2 to 7.
  • R 4 is hydrogen, triethylammonium, trialkylsilyl of 1 to 6 carbon atoms, or an alkali metal cation,
  • R 1 , R 2 , R 3 and n are as above defined, and X is hydroxyl or a reactive group which is split off in the acylation of the amino group.
  • the penicillins of the present invention are useful for their antibacterial activity, and, in particular, exhibit greater antibacterial activity against certain microorganisms than do commercially available products such as Penicillin G, Penicillin V or Azidocillin.
  • 6-(3-chloro-cyclobutylcarboxamido)-penicillanic acid (V) is obtained as its sodium salt.
  • R 1 is hydrogen, chlorine, or bromine; or, when R 2 is hydrogen, R 1 is hydrogen, chlorine, bromine or cyano;
  • R 2 is hydrogen, chlorine or bromine.
  • R 1 and R 2 are the same moiety.
  • R 1 and R 2 together with a ring carbon atom, form a carbonyl group
  • R 3 is hydrogen, methyl, chlorine, bromine or cyano.
  • R 1 and R 2 are the same or different and each is hydrogen fluorine, chlorine, or bromine; or when R 2 is hydrogen, R 1 can also be cyano; or
  • R 1 and R 2 together with a ring carbon atom, form a carbonyl group
  • R 3 is hydrogen, methyl or chlorine
  • n 2, 3, 4, 5, or 6.
  • R 1 and R 2 are the same or different and each is hydrogen, chlorine, or bromine; or, when R 2 is hydrogen, R 1 can also be cyano; or
  • R 1 and R 2 together with a ring carbon atom, form a carbonyl moiety
  • R 3 is hydrogen, methyl, chlorine, bromine or cyano
  • n 2, 3, 4 or 5.
  • the alkyl moieties may be either the same or different. Preferably, they are the same. Methyl, ethyl and n-propyl are preferred with methyl being particularly preferred. When R 4 is an alkali metal cation, sodium and potassium are particularly preferred.
  • n is preferably to 2 to 5.
  • X When X is a reactive group which is split off during the course of the acylation of the amino group, X can, for example, be azido; alkoxy, preferably of 1 to 6 and especially of 1 to 4 carbon atoms, unsubstituted or substituted by cyanomethoxy or a --O--COY moiety wherein Y is alkyl, especially of 1 to 4 carbon atoms; aryl, for example, phenyl; alkoxy, preferably of 1 to 4 carbon atoms and particularly methoxy or ethoxy. It is especially preferred that X is halogen, especially chlorine or bromine.
  • the salts of the penicillins of formula I include the salts formed at the acid carboxyl group with inorganic or organic bases and ammonia.
  • Representative bases include: alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates, such as sodium, potassium, magnesium and calcium hydroxide, sodium, potassium and calcium carbonate, sodium and potassium bicarbonate and aluminum hydroxide.
  • Representative salts formed with inorganic bases include sodium, potassium, magnesium, calcium, aluminum and ammonium salts.
  • Salts formed with amines include di- and tri- alkylamines such as triethylamine, ethanolamine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-benzyl- ⁇ -phenylethylamine, N-methylmorpholine and N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N,N'-bis-dehydroabietylethylenediamine and N-alkylpiperidines.
  • di- and tri- alkylamines such as triethylamine, ethanolamine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-benzyl- ⁇ -phenylethylamine, N-methylmorpholine and N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N,N'-bis-dehydroabietylethylenediamine and N-alkylpiperid
  • the compounds of formula II which are used as starting materials according to the above process are known in the art. They may be obtained from Penicillin G by fermentative of chemical processes such as are described in German Auslegeschrift No. 1,111,778 and in Doyle, Nayler and Rolinson, British Patent No. 870,396 (1961) and in F. R. Batchelor et al., Nature (London), 183, 257 (1959).
  • Hal is halogen; for example, chlorine or bromine
  • R 5 is methyl or ethyl
  • R 6 is hydrogen or methyl: ##SPC9##
  • Representative starting materials of formula III include:
  • the compounds of formula III can be used either as cis/trans isomer mixtures or in the pure stereoisomeric forms, i.e., the cis or the trans form.
  • a diluent which is generally an organic solvent.
  • suitable diluents include alkylketones (for example, acetone), ethers (for example, tetrahydrofuran (THF) and dioxane), alkylnitriles (for example, acetonitrile), dimethylformamide (DMF), dimethylsulphoxide, halogenated hydrocarbons (for example, methylene chloride), and mixtures of these solvents with one another and with water.
  • any acid-binding agent can be used.
  • Suitable agents include inorganic and organic bases, such as alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates (for example, sodium, potassium or calcium hydroxide, sodium, potassium or calcium carbonate or sodium or potassium carbonate), aliphatic amines (for example, triethylamine), and heterocyclic bases (for example, N-methyl-morpholine).
  • the pH value of the reaction mixture can be maintained, by continuous or incremental addition of these bases, at any desired value, preferably at pH 6.5 to 9.2
  • reaction temperatures can be varied within a substantial range. In general, the reaction is carried out at between -20° C and +50° C, and preferably between -15° C and + 20° C.
  • the reaction can be carried out under atmospheric pressure but also under elevated pressure. In general, atmospheric pressure is used.
  • the reactants are preferably reacted with one another in equimolecular amounts.
  • the reactants of the formula III can be employed in an excess of 10 to 30 per cent.
  • the new free penicillin of the formula I and their salts can be interconverted in any suitable manner; methods for such interconversion are known in the art.
  • isolation and, if desired, purification of the compounds of the invention are carried out in a known manner in accordance with generally customary methods of organic chemistry.
  • the compounds of the present invention are characterized by strong antimicrobial activity and low toxicity. They are thus useful for the treatment of a broad range of Gram-positive and Gram-negative bacterial infections. They are also useful for preserving organic and inorganic materials such as polymers, lubricants, paints, fibers, leather, paper, timer, foodstuffs, water and the like.
  • Compounds of the present invention are particularly useful for the prophylaxis and treatment of topical and systemic infections caused by Gram-positive and Gram-negative microorganisms.
  • Corynebacteriaceae such as Corynebacteria (for example, Corynebacterium diphtheriae, C, pyogenes, C. diphtheroides, C. acnes, C. parvum, C. bovis, C. renale, C. ovis and C. murisepticum);
  • Corynebacteria for example, Corynebacterium diphtheriae, C, pyogenes, C. diphtheroides, C. acnes, C. parvum, C. bovis, C. renale, C. ovis and C. murisepticum
  • Enterobacteriaceae such as Escherichiae bacteria, (for example, Escherichia coli), Enterobacter bacteria (for example, E. aerogenes and E. cloacae)
  • E.” Enterobacter
  • Klebsiella bacteria for example, K. pneumoniae
  • K.” Klebsiella
  • Erwiniae for example, Erwinia spec.
  • Serratia for example, Serratia marcescens, Proteae bacteria of the Proteus group: Proteus (for example,
  • Pasteurella bacteria for example, Pasteurella multocida, Past, pestis (Yersinia), Past, pseudotuberculosis
  • Illnesses of the respiratory passages, the pharyngeal cavity, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis, and arthritis may all be treated with the penicillins of the present invention.
  • Table 1 which follows, specifies the minimum inhibitory concentrations (MIC) in vitro, in U/ml of nutrient medium of typical compounds of the invention. They were determined in a liquid medium in a test tube series dilution test, the readings being taken after 24 hours incubation at 37° C.
  • the MIC is indicated by the non-turbid test tube in the dilution series.
  • a complete medium of the following composition was used as the growth medium:
  • the compounds of the present invention are active against genera of bacteria other than those mentioned in Table 1. This shown by the following experiment which was carried out with the compound of Example 1.
  • the compound of Example 1 was diluted with Muller-Hinton nutrient broth, with addition of 0.1% of glucose, to a content of 100 ⁇ g/ml.
  • the nutrient solution contained 1 ⁇ 10 5 to 2 ⁇ 10 5 bacterial cells per milliliter.
  • E. coli BE Salmonella sp.;Shigella sp.; Proteus indolnegativ, sp.; Pasteurella pseudotuberculosis; Brucella sp.;
  • Table 2 which follows, shows the action of one of the compounds of the present invention against a series of bacteria in animal experiments in white mice.
  • the white, mice of strain CF 1 were infected intraperitoneally with the particular species of bacteria indicated.
  • Treatment l administration 30 minutes after infection
  • the ED 50 is the dose at which 50% of the infected animals still survive after 24 hours.
  • compositions of the present invention contain a major or minor amount, e.g. 0.1% to 99.5%, preferably 0.5% to 95% of active ingredient as above defined in combination with a pharmaceutically acceptable, nontoxic, inert diluent or carrier, the carrier comprising one or more solid, semi-solid or liquid diluent, filler and formulation adjuvant which is nontoxic, inert and pharmaceutically acceptable.
  • a pharmaceutically acceptable, nontoxic, inert diluent or carrier the carrier comprising one or more solid, semi-solid or liquid diluent, filler and formulation adjuvant which is nontoxic, inert and pharmaceutically acceptable.
  • Such pharmaceutical compositions are preferably in dosage unit form; i.e., physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response.
  • the dosage units can contain one, two, three, four or more single doses or, alternatively, one half, third or fourth of a single dose.
  • a single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to a predetermined dosage regimen, usually a whole, half, third or quarter of the daily dosage administered once, twice, three or four times a day.
  • Other therapeutic agents can also be present.
  • the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the router of administration and the nature and gravity of the illness, generally the dosage will be from 6 to 900, preferably 20 to 300, mg/kg of body weight per day. In some instances, a sufficient therapeutic effect can be obtained at a lower dose; while in others, a larger dose will be required. Individual administrations are preferably from 2 to 300, especially 5 to 100, mg/kg of body weight.
  • Oral administration can be effected utilizing solid and liquid dosage unit forms such as powders, tablets, dragees, capsules, granulates, suspensions, solutions and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch, lactose, sucrose, glucose or mannitol. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.
  • a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch, lactose, sucrose, glucose or mannitol.
  • Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improved the availability of the medicament when the capsule is ingested.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base, as described above, and, optionally, with a binder such as carboxymethyl cellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethyl cellulose, an alginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the medicaments can also be combined with free-flowing, inert carriers and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution, while elixirs are prepared through the use of a nontoxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a nontoxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, flavor additives such as pepperming oil or saccharin, and the like, can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax or the like.
  • Parenteral administration can be effected utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a nontoxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively, a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration. Non-toxic salts and salt solutions can be added to render the injection isotonic. Stabilizers, preservatives and emulsifiers can also be added.
  • Rectal administration can be effected utilizing suppositories in which the compound is admixed with low-melting, water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher esters as, for example, myristyl palmitate, or mixtures thereof.
  • low-melting, water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher esters as, for example, myristyl palmitate, or mixtures thereof.
  • Topical administration can be effected utilizing solid dosage unit forms such as powders or liquid or semi-liquid dosage unit forms such as solutions, suspensions, ointments, pastes, creams and gels.
  • the powders are formulated utilizing such carriers as talc, bentonite, silicic acid, polyamide powder and the like.
  • Liquid and semi-liquid formulations can utilize such carriers, in addition to those described above, as polyethylene glycol, vegetable and mineral oils, alcohols such as isopropanol and the like. Other excipients such as emulsifiers, preservatives, colorants, perfumes and the like can also be present.
  • Formulations can also be administered as an aerosol, utilizing the usual propellants such as the chlorofluorohydrocarbons.
  • the preferred daily dose is 300 mg. to 90 g, preferably 1 g to 20 g of active agent.
  • routes of administration include oral, parenteral (i.e., intramuscular, intraperitoneal and intravenous), rectal, and topical, particularly preferred is parenteral administration, especially intravenous.
  • the preferred pharmaceutical compostions are therefore those in a form suitable for parenteral administration such as injectable (i.e., sterile and isotonic) solutions and ampoules of such solutions.
  • compositions of the present invention are also useful against penicillinase-producing bacteria.
  • penicillins may be included such as prostaphin, i.e., Oxacillin and Dicloxacillin.
  • the ⁇ -lactam content of the compounds prepared was determined iodometrically.
  • the compounds produced were subjected to an analytical counter-currrent distribution through 29 steps, using petroleum ether/ethyl acetate/dimethylformamide/water as the distribution system.
  • the water content of the 6-APA drivatives is taken into account.
  • A. 7 g (0.0323 mol) of 6-aminopenicillanic acid (6-APA) are suspended in a mixture (120 ml) of THF and water (1:1).
  • the suspension is adjusted to pH 7.8 to 8.0 by means of 2 N NaOH, while cooling with ice, and 6.95 g (0.0371 mol) of 2,2-dichloro-1-methyl-cyclopropanecarboxylic acid chloride dissolved in 35 ml of pure THF are added over the course of 25 minutes at +2° C to +5° C.
  • the pH value of the reaction solution is kept at 7.2-7.5 up to the end of the experiment by further addition of 2 N sodium hydroxide solution.
  • the reaction mixture is stirred for a further 20 minutes at +5° C and 20 minutes at +15° C.
  • the residual solution is diluted with 200 ml of water and extracted once with ethyl acetate (EA).
  • the aqueous phase which has been separated off, is cooled to 0° C, covered with 200 ml of EA, with addition of 70 ml of methyl ethyl ketone, and acidified to a pH value of 2.0 with 2 N HCl.
  • the organic phase is separated off and the aqueous phase is extracted once more with 150 ml of EA.
  • the end product is isolated by vacuum distillation.
  • the sodium salt of the penicillin is prepared analogously to Example 1A from: 6 g (0.0278 mol) of 6-APA and 9.2 g (0.0332 mol) of 2,2-dibromo-1-methyl-cyclopropanecarboxylic acid chloride.
  • the substituted cyclopropanecarboxylic acid is prepared analogously to Example 1B from 100 g (1mol) of methyl acrylate and 253 g (1 mol) of bromoform in the presence of 102 ml (1.27 mols) of 50% strength sodium hydroxide solution and 4 g (0.0176 mol) of benzyltriethyl-ammonium chloride.
  • Boiling point (0.2 mm.Hg) : 115°-120° C
  • the substituted cyclopropanecarboxylic acid chloride is prepared analogously to Example 1C from 35 g (0.136 mol) of 2,2-dibromo-1-methyl-cyclopropanecarboxylic acid and 110 ml of thionyl chloride in the presence of CH 2 Cl 2 .
  • the sodium salt of this penicillin is prepared analogously to Example 1A from; 4.88 g (0.0226 mol) of 6-APA and 3.2 g (0.0248 mol) of 2-cyano-1-cyclopropanecarboxylic acid chloride.
  • the acid chloride is prepared analogously to Example 1C from 11.7 g (0.105 mol) of 2-cyano-1-cyclopropanecarboxylic acid and 80 ml of SOCl 2 .
  • the sodium salt of this penicillin is prepared by a method based on Example 1A, from: 6.5 g (0.0301 mol) of 6-APA and 5.05 g (0.033 mol) of 3-chloro-1-cyclobutanecarboxylic acid chloride.
  • the sodium salt is recrystallized from a small amount of chloroform and a large amount of diisopropyl ether.
  • Boiling point (10 mm.Hg) 125°-130° C.
  • the acid chloride is prepared analogously to Example 1C from 3 g (0.0223 mol) of 3-chloro-1-cyclobutanecarboxylic acid and 20 ml of thionyl chloride in the presence of 20 ml of CH 2 Cl 2 .
  • the sodium salt of this penicillin is prepared analogously to Example 1A form: 7.00 g (0.0323 mol) of 6-APA and 5.32 g (0.0379 mol) of 1-cyano-1-cyclobutanecarboxylic acid chloride.
  • the acid chloride is prepared analogously to Example 1C from 9.5 g (0.076 mol) of 1-cyano-1-cyclobutanecarboxylic acid and 60 ml of SOCl 2 .
  • the sodium salt of this penicillin is prepared analogously to Example 1A from: 5.0 g (0.0232 mol) of 6-APA and 4.65 g (0.0278 mol) of 4-chloro-1-cyclopentanecarboxylic acid chloride.
  • 3rd fraction contains some 3,4-dichloro-1-cyclopentanecarboxylic acid; substance was discarded.
  • the acid chloride is prepared analogously to Example 1C from 12.9 g (0.0868 mol) of 4-chloro-1-cyclopentanecarboxylic acid and 85 ml of thionyl chloride in the presence of CH 2 Cl 2 .
  • the sodium unit salt of this penicillin is prepared analogously to Example 1A from: 4.32 g (0.02 mol) of 6-APA and 4.8g. (0.0239 mol) of 3,4-dichloro-1-cyclopentanecarboxylic acid chloride. After recrystallization from THF/ether, 6.4 g (80.6%) of the sodium salt of 6-(3,4-dichlorocyclopentylcarboxamido)-penicillanic acid are obtained.
  • the acid chloride is prepared analogously to Example 1C from 4.5 g (0,0246 mol) of 3,4-dichloro-1-cyclopentanecarboxylic acid (see Example 6B) and 80 ml of thionyl chloride in the presence of CH 2 Cl 2 .
  • Gas chromatogram single substance (Column: 2 m long, 2 mm ⁇ ; carrier material Chromosorb W; 100-120 mesh; liquid phase; silicone oil; isothermal oven: 150° C).
  • the sodium salt of this penicillin is prepared analogously to Example 1A from: 8 g (0.037 mol) of 6-APA and 8.05 g (0.0443 mol) of cyclopentanone-2-chloro-2-carboxylic acid chloride.
  • the acid chloride is prepared analogously to Example 1C from 9 g (0.0554 mol) of cyclopentanone-2-chloro-2-carboxylic acid and 80 ml of SOCl 2 .
  • the sodium salt of this penicillin is prepared analogously to Example 1A from: 4.9 g (0.0227 mol) of 6-APA and 5.0 g (0.0272 mol) of 4-chloro-1-cyclohexanecarboxylic acid chloride.
  • the acid chloride is prepared analogously to Example 1C from 9.7 g (0.0595 mol) of 4-chloro-1-cyclohexanecarboxylic acid dissolved in 50 ml of CH 2 Cl 2 and 60 ml of SOCl 2 .
  • the sodium salt of this penicillin is prepared analogously to Example 1A from 6 g (0.0277 mol) of 6-APA and 6.9 g (0.032 mol) of 4,5-dichloro-1-cyclohexanecarboxylic acid chloride
  • the acid chloride is prepared by a method based on Example 1C from 14.6 g (0.074 mol) of 4.5-dichloro-1-cyclohexanecarboxylic acid and 60 ml SOCl 2 in 50 ml of CH 2 Cl 2 .
  • the sodium salt of this penicillin is prepared analogously to Example 1 from: 6 g (0.0277 mol) of 6-APA and 7.04 g (0.0333 mol) of 1-bromo-1-cyclopentanecarboxylic acid chloride.
  • the acid chloride is prepared analogously to Example 1C from 10 g (0.0518 mol) of 1-bromo-1-cyclopentanecarboxylic acid dissolved in 30 ml of CH 2 Cl 2 and 50 ml of SOCl 2 .
  • the sodium salt of this penicillin is prepared analogously to Example 1A from: 6 g (0.0277 mol) of 6-APA and 6.02 g (0.0332 mol) of 1-chloro-cyclohexanecarboxylic acid chloride.
  • Boiling point (14 mm.Hg): 95°-110°C
  • the solution is extracted four times with ether, the extracts washed with 10% NaHCO 3 -solution.
  • the NaHCO 3 -phase is now carefully acidified with half-concentrated HCl and again extracted with ether.
  • the combined ethereal extracts are dried directly over Na 2 SO 4 , then Na 2 SO 4 is separated off, the solvent evaporated i.v., and the residue distilled in high vacuum.
  • the acid chloride is prepared from 12 g (0.0776 mol) 2,2-dichloro-Cyclopropanecarboxylic acid and 40 ml SOCl 2 in 50 ml CH 2 Cl 2 .
  • Example 13C Analogously to Example 13C the oxidation of the vinyl-cyclopropane derivative (67.8 g; 0.3 mol) is carried out in 425 ml acetone by means of 8.46 g NaHCO 3 and 166 g KMnO 4 .
  • the crude product is triturated in n-pentane and thus brought to crystallization.
  • the acid chloride is prepared from 10 g (0.0411 mol) 2,2-dibromo-cyclopropanecarboxylic acid and 50 ml SOCl 2 in 30 ml CH 2 Cl 2 .
  • the acid chloride is prepared from 17.8 g (0.086 mol) 1-bromo-1-cyclohexane-carboxylic acid dissolved in CH 2 Cl 2 and 60 ml. SOCl 2 .

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  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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US05/516,359 1973-10-25 1974-10-21 6-(Substituted-cycloalkylcarboxamide) penicillanic acids Expired - Lifetime US3954730A (en)

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DE19732353584 DE2353584A1 (de) 1973-10-25 1973-10-25 Penicilline, ein verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittal
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AT (1) AT332972B (fr)
BE (1) BE821477A (fr)
CA (1) CA1046504A (fr)
CH (1) CH608017A5 (fr)
DE (1) DE2353584A1 (fr)
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ES (1) ES431324A1 (fr)
FI (1) FI310074A7 (fr)
FR (1) FR2248836B1 (fr)
GB (1) GB1459949A (fr)
IE (1) IE40190B1 (fr)
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US4127570A (en) * 1970-09-25 1978-11-28 Beecham Group Limited β-Aminopenicillins, salts and esters
US4389407A (en) * 1980-07-15 1983-06-21 Ausonia Farmaceutici S.R.L. 1,3-Thiazolidin-4-yl-carboxylic acid derivatives and antibacterial compositions thereof
WO2005019158A1 (fr) * 2003-08-12 2005-03-03 Boehringer Ingelheim International Gmbh Composes d'acide 1-carbamoylcycloalkylcarboxylique, procedes de fabrication et d'utilisation associes

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US3041333A (en) * 1960-05-11 1962-06-26 Smith Kline French Lab Substituted cyclopropylcarboxyamido derivatives of penicillanic acid
US3174964A (en) * 1959-12-10 1965-03-23 Pfizer & Co C Derivatives of 6-aminopenicillanic acid
US3245983A (en) * 1959-01-22 1966-04-12 Beecham Group Ltd 6-(alpha, alpha, alpha-trisubstituted-acetamido) penicillanic acids and salts thereof
US3494915A (en) * 1967-07-28 1970-02-10 American Home Prod 6-(indan - 2 - amino - 2 - carboxamido) and 6 - (1,2,3,4 - tetrahydronaphthalene - 2-amino - 2 - carboxamido) penicillanic acids
US3532744A (en) * 1967-07-28 1970-10-06 American Home Prod 1- and 2-amino substituted indane and tetralene carboxylic acids
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US3553201A (en) * 1967-10-03 1971-01-05 American Home Prod Dehydrated crystalline 6-(1-aminocyclo-alkylcarboxamido) penicillanic acids
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US3174964A (en) * 1959-12-10 1965-03-23 Pfizer & Co C Derivatives of 6-aminopenicillanic acid
US3041333A (en) * 1960-05-11 1962-06-26 Smith Kline French Lab Substituted cyclopropylcarboxyamido derivatives of penicillanic acid
US3573279A (en) * 1967-01-25 1971-03-30 American Home Prod 1-substituted cycloalkyl penicillins
US3494915A (en) * 1967-07-28 1970-02-10 American Home Prod 6-(indan - 2 - amino - 2 - carboxamido) and 6 - (1,2,3,4 - tetrahydronaphthalene - 2-amino - 2 - carboxamido) penicillanic acids
US3532744A (en) * 1967-07-28 1970-10-06 American Home Prod 1- and 2-amino substituted indane and tetralene carboxylic acids
US3553201A (en) * 1967-10-03 1971-01-05 American Home Prod Dehydrated crystalline 6-(1-aminocyclo-alkylcarboxamido) penicillanic acids
US3538083A (en) * 1967-12-19 1970-11-03 American Home Prod Synthetic method for preparing penicillins

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4127570A (en) * 1970-09-25 1978-11-28 Beecham Group Limited β-Aminopenicillins, salts and esters
US4389407A (en) * 1980-07-15 1983-06-21 Ausonia Farmaceutici S.R.L. 1,3-Thiazolidin-4-yl-carboxylic acid derivatives and antibacterial compositions thereof
WO2005019158A1 (fr) * 2003-08-12 2005-03-03 Boehringer Ingelheim International Gmbh Composes d'acide 1-carbamoylcycloalkylcarboxylique, procedes de fabrication et d'utilisation associes
US20050085544A1 (en) * 2003-08-12 2005-04-21 Boehringer Ingelheim International Gmbh Cycloalkylamidoacid compounds, processes for making and uses thereof
US7550622B2 (en) 2003-08-12 2009-06-23 Boehringer Ingelheim International Gmbh Cycloalkylamidoacid compounds, processes for making and uses thereof

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IE40190B1 (en) 1979-03-28
SE7413409L (fr) 1975-04-28
DK558174A (fr) 1975-06-16
FR2248836A1 (fr) 1975-05-23
BE821477A (fr) 1975-04-25
JPS5068869A (fr) 1975-06-09
IE40190L (en) 1975-04-25
CA1046504A (fr) 1979-01-16
JPS5070388A (fr) 1975-06-11
ES431324A1 (es) 1976-11-01
LU71164A1 (fr) 1975-06-24
CH608017A5 (fr) 1978-12-15
ATA860174A (de) 1976-02-15
NL7413824A (nl) 1975-04-29
ZA746755B (en) 1975-11-26
DE2353584A1 (de) 1975-05-07
FR2248836B1 (fr) 1978-07-28
GB1459949A (en) 1976-12-31
AT332972B (de) 1976-10-25
FI310074A7 (fr) 1975-04-26

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